Genetic and epigenetic drivers of neuroendocrine tumours (NET)

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   Figure 1

   Mutation rate in NET. Graphical representation of the number of exonic non-silent mutations in non-functional pancreatic NETs (NF-pNETs), insulinomas (Ins), lung NETs and small intestinal NETs (SI-NETs) compared to pancreatic ductal adenocarcinomas (PDAC) and lung adenocarcinomas (LAC). Each dot represents a single tumour. (Data merged from: Jiao et al. 2011, Cao et al. 2013, Francis et al. 2013, Cancer Genome Atlas Research 2014, Fernandez-Cuesta et al. 2014, Cromer et al. 2015, Lichtenauer et al. 2015, Witkiewicz et al. 2015, Scarpa et al. 2017).
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   Figure 2

   Mutated genes and relative affected pathways in NETs. (A) Pancreatic NET. (B) Small Intestinal NET. (C) Pulmonary NET.
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   Figure 3

   Cellular functions affected by gene mutations in pancreatic, pulmonary and small intestinal NET. Different colours represent different tumours: orange for Small Intestinal NETs (SI-NETs), green for Lung NETs and blue for pancreatic NETs (PanNETs). The intensity of the colours indicates the frequency (Dark: high frequency, Light: low frequency). The majority of the mutations in pulmonary and pancreatic NET are found in genes encoding for chromatin stability and remodelling, while fewer mutations are found in genes involved in cell cycle, gene expression and angiogenesis.
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   Figure 4

   Graphic representation of tumorigenic mechanisms associated with DAXX and ATRX loss in pancreatic NET. DAXX and ATRX are involved in the epigenetic regulation. DAXX and ATRX loss may induce a reduction in DNA methylation at telomeric regions facilitating DNA recombination thus activating ALT. DAXX and ATRX loss may also induce hypo-methylation of repetitive elements enhancing CIN. On the other hand, DAXX and ATRX loss impact on the methylation status of several regions affecting gene expression. ALT, Alternative Lengthening Telomeres; CIN, Chromosomal Instability; DNMT, DNA methyltransferase; LINE1, Long Interspersed Element.

• © 2017 Society for Endocrinology